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Exploiting Transaminases and Amine Oxidases for the Synthesis of Enantiomerically Pure Compounds of Biological Relevance

Brzezniak, Agata

[Thesis]. Manchester, UK: The University of Manchester; 2019.

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Abstract

Efficient generation of amine-bearing privileged structures represents a cornerstone of modern organic chemistry. Such compounds can be employed for the preparation of drug targets or compound libraries suitable for biological screening. Application of biocatalysis in organic synthesis allows for a more sustainable manufacture of enantiomerically pure privileged scaffolds. The key aim of this research project was to utilise the existing toolbox of transaminase and monoamine oxidase enzymes in the preparation of biologically important compounds. Firstly, chiral key amine intermediates were successfully obtained in high yields and enantiomeric excess from biotransformations of (S)-selective ATA-113 and MAO-N D9 enzyme variants, which allowed for the subsequent synthesis of JAK2/STAT3 signalling pathway inhibitors. The resulting racemic, (S)- and (R)- configured alkyne analogues of WP1066 were evaluated for their biological activities including the determination of their anti-proliferative activities against aggressive MDA- MB-231 breast cancer cell line (IC50 = ~600 nM for all variants). Secondly, the chemoenzymatic approach to hygrine and tropinone natural products was attempted using putrescine transaminase and monoamine oxidase biocatalysts, respectively. The dehydrohygrine framework was the unexpected product resulting from monoamine oxidase oxidation of hygrine. Additionally, quinolizidine scaffolds present in xestospongin and petrosin natural products were synthesised using the Polonovski-Potier reaction and their tertiary amine precursors were screened against existing amine oxidases. Lastly, a keramaphidin B analogue was successfully synthesised using a biomimetic approach providing evidence for the manzamine biosynthesis hypothesis. The potential of amine oxidase biocatalysts was also further demonstrated in the preparation of the same keramaphidin B framework using a biocatalytic methodology.

Bibliographic metadata

Type of resource:
Content type:
Administered thesis
Form of thesis:
Traditional
Type of submission:
Doctoral level ETD - final
Thesis title:
Exploiting Transaminases and Amine Oxidases for the Synthesis of Enantiomerically Pure Compounds of Biological Relevance
Degree type:
Doctor of Philosophy
Degree programme:
BBSRC Doctoral Training Programme Chemistry
Publication date:
2019-02-22T11:12:14
Institution:
The University of Manchester
Location:
Manchester, UK
Total pages:
236
Abstract:
Efficient generation of amine-bearing privileged structures represents a cornerstone of modern organic chemistry. Such compounds can be employed for the preparation of drug targets or compound libraries suitable for biological screening. Application of biocatalysis in organic synthesis allows for a more sustainable manufacture of enantiomerically pure privileged scaffolds. The key aim of this research project was to utilise the existing toolbox of transaminase and monoamine oxidase enzymes in the preparation of biologically important compounds. Firstly, chiral key amine intermediates were successfully obtained in high yields and enantiomeric excess from biotransformations of (S)-selective ATA-113 and MAO-N D9 enzyme variants, which allowed for the subsequent synthesis of JAK2/STAT3 signalling pathway inhibitors. The resulting racemic, (S)- and (R)- configured alkyne analogues of WP1066 were evaluated for their biological activities including the determination of their anti-proliferative activities against aggressive MDA- MB-231 breast cancer cell line (IC50 = ~600 nM for all variants). Secondly, the chemoenzymatic approach to hygrine and tropinone natural products was attempted using putrescine transaminase and monoamine oxidase biocatalysts, respectively. The dehydrohygrine framework was the unexpected product resulting from monoamine oxidase oxidation of hygrine. Additionally, quinolizidine scaffolds present in xestospongin and petrosin natural products were synthesised using the Polonovski-Potier reaction and their tertiary amine precursors were screened against existing amine oxidases. Lastly, a keramaphidin B analogue was successfully synthesised using a biomimetic approach providing evidence for the manzamine biosynthesis hypothesis. The potential of amine oxidase biocatalysts was also further demonstrated in the preparation of the same keramaphidin B framework using a biocatalytic methodology.
Keyword(s):
Thesis main supervisor(s):
Thesis co-supervisor(s):
Funder(s):
Degree grantor:
Language:
en

Institutional metadata

University researcher(s):
Academic department(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:318487
Created by:
Brzezniak, Agata
Created:
22nd February, 2019, 11:12:14
Last modified by:
Brzezniak, Agata
Last modified:
2nd March, 2020, 11:00:37

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